It is often found necessary to process bulk drug substance to improve its properties prior to further processing into final product form. Options include melt-extrusion, spray drying and various types of milling. This may be for one or more of several reasons, for instance, to improve processability or to improve bioavailability.
It is often found helpful to subject poorly soluble compounds to milling, either by a dry process such as micronisation, or in the presence of a liquid (typically aqueous), to decrease particle size, thereby improving the dissolution rate and bioavailability of the compound by increasing the surface area (Mura et al, 2001, Drug Development and Industrial Pharmacy 27 (2): 119-128). Such milling however requires a significant amount of energy and this can lead to unwanted solid state transitions such as a polymorphic conversion or amorphous formation (Brittain, 2002, Journal of Pharmaceutical Sciences 91 (7): 1573-1580). In some instances, however, it may be useful to deliberately induce amorphous form conversion, not only of neat drug substance but also drug:polymer blends, see for instance the work of Boldyrev et al (1994, Drug Development and Industrial Pharmacy 20 (6): 1103-1113) on ball milling of sulfathiazole and PVP which resulted in the formation of a glass solution. Prolonged milling can result in the drug substance absorbing the excess free enthalpy and this can lead to an acceleration not only of physical reactions but also of undesirable chemical reactions (Huttenrauch et al, 1985, Pharmaceutical Research 2: 302-306).
There are a number of process variables involved in a milling process which can influence the physical form of the product such as temperature, grinding media, frequency and duration. Thus, the temperature at which milling is performed has been shown to influence the physical form of the final milled product. Milling of a drug:polymer system under dry conditions results in significant generation of heat. Masumoto et al (1988, Pharmaceutical Research 16 (11): 1722-1728) ball milled phenylbutazone at different temperatures (4° C. and 35° C.). Milling temperature was reported to influence the polymorphic form of the final product. Otsuka et al (1986, Chem Pharm Bull (Tokyo). 34 (4):1784-93) found that milling temperature (4° C. and 30° C.) influenced the duration of milling required to convert the α and γ indomethacin polymorphs to the amorphous form. Crowley and Zografi (2002, Journal of Pharmaceutical Sciences 91 (2): 492-507) showed that ball milling indomethacin in a vessel submerged in liquid nitrogen (cryogenic impact mill) resulted in amorphous conversion. Ball milling has also been carried out with liquid nitrogen in direct contact with the drug substance (Geze et al, 1999, International Journal of Pharmaceutics 178 (2): 257-268).
The physical state of the milled product is also influenced by formulation variables. Thus, the addition of amorphous polymers such as PVP can increase the amorphous conversion of a compound. Mura et al (2002, Journal of Pharmaceutical and Biomedical Analysis 30 (2): 227-237) found that when glisentide was milled with PVP, the time and frequency of milling necessary to obtain an amorphous product was decreased. Boldyrev et al (1994) found that increasing the proportion of PVP and milling resulted in a decrease in crystalline nature of the product.
An aspect of milling in the presence of a liquid (typically aqueous), is the need to recover and then dry the resultant milled drug substance from the suspension. Filtration is often difficult. Spray drying may be used to avoid these problems, but efficient isolation of the very fine particles may still be difficult. In addition, spray drying on a large scale requires substantial capital investment, is energy intensive and produces large volumes of solvent which have to be dealt with.
Ball milling at low temperatures has been reported. Thus, for instance, Geze et al (ibid) milled 5-iodo-2′-deoxyuridine in the presence of liquid nitrogen in the sample vessel, resulting in decreased mean particle size and narrower particle size distribution.
Lizio et al (AAPS PharmSciTech 2001, 2 (3), article 12) describe the low temperature micronisation of a peptide drug in a fluid propellant (heptafluoropropane) in a modified pearl-mill coupled to a cryostat, at temperatures of −50 and −90 deg C.
WO2005/053851 (E I DuPont De Nemours and Company, published 16 Jun. 2005, after the priority date of the present application) describes a high pressure media milling system and process of milling particles, to provide fine and ultra-fine particles.
The main focus is milling in supercritical carbon dioxide. Example 3 however describes the media milling of lactose crystals in a pressurised pharmaceutical propellant, HFC-134a, in the presence of a surfactant, sorbitan mono-oleate. There is however no discussion on the physical form of the resultant milled material.
It has now been found that co-milling in a liquid propellant in the presence of a pharmaceutically acceptable polymer can have a beneficial influence on the physical state of the drug substance in the milled product, in particular in promoting the crystalline form of the drug substance, rather than the amorphous form, as might otherwise have been predicted.